Inhibiting Fructose Metabolism Slows Pancreatic Cancer

The Stoffel lab and collaborators investigated the role of fructose metabolism and the rate limiting enzyme involved therein, called ketohexokinase. They could show that a fructose containing diet worsened pancreatic cancer progression in a  mouse model. Genetic knock-out of ketohexokinase isoform C slows pancreatic cancer cell progression likely by rewiring cancer-metabolism related pathways. Their findings have been published in the article "Genetic ablation of ketohexokinase C isoform impairs pancreatic cancer development" in iScience.


  • Fructose enhances proliferation and decreases the survival of mice with PDAC
  • KHKC overexpression promotes pancreatic tumor growth
  • Pancreatic ablation of KhkC dampens the proliferation of KPC driven tumors
  • Pancreatic KhkC inactivation rewires PDAC metabolism-related pathways

Although dietary fructose is associated with an elevated risk for pancreatic cancer, the underlying mechanisms remain elusive. Here, we report that ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, is a driver of PDAC development. We demonstrate that fructose triggers KHK and induces fructolytic gene expression in mouse and human PDAC. Genetic inactivation of KhkC enhances the survival of KPC-driven PDAC even in the absence of high fructose diet. Furthermore, it decreases the viability, migratory capability, and growth of KPC cells in a cell autonomous manner. Mechanistically, we demonstrate that genetic ablation of KHKC strongly impairs the activation of KRAS-MAPK pathway and of rpS6, a downstream target of mTORC signaling. Moreover, overexpression of KHKC in KPC cells enhances the downstream KRAS pathway and cell viability. Our data provide new insights into the role of KHK in PDAC progression and imply that inhibiting KHK could have profound implications for pancreatic cancer therapy.

Read the Publication in iScience (Open Access)

Website Stoffel Lab

Figures, highlights, summary and title from Guccini et al (2023) iScience published under a CC BY 4.0 license.